Development of novel vaccines against drug abuse - Proof of concept study for vaccines against nicotine addiction Project Summary Drug abuse is a growing global problem particularly in the United States. The addiction of psychoactive drugs has caused significant social and economical stresses. Among all drugs, tobacco, cocaine, and heroin are the most addictive ones. Tobacco is the most widely abused substance, yet smoking is legal and causes arguably the most serious health-related problems in the United States and around the world. Chronic use of tobacco is considered a responsible factor for serious diseases such as chronic obstructive pulmonary disease, stroke, chronic lung disease, and cancer. There are more than 60 million smokers currently in the U.S. and 400,000 related deaths per year. In addition, there are more than 2 million American abusers of heroin and cocaine. Due to the nature of the chemicals (as small molecules), finding ways to combat the problem has been a constant challenge to the society and the medical field. Current pharmacological therapies have shown very limited success with some accompanying serious side-effects, such as depression with suicidal behavior. On the other hand, immunopharmacotherapy has emerged as a promising alternative to combat drug addiction. Evidently, the success of drug vaccines is directly correlated with the antibody titer in the vaccinated subjects. All current vaccines, particularly the three in human clinical trials, have shown limited efficacy depending on the vaccine's ability to elicit antibody response, and thus there is undoubtedly a need for improved nicotine vaccines that can elicit strong immune response. In this project, we propose an unprecedented approach to develop potentially very potent vaccines against small molecule drugs. As a model study, we propose to develop vaccines against nicotine addiction. The innovation of this project involves the use of a new class of carbon nanomaterial, nanohorn, as support for lipid and carrier protein assembly. The carrier protein will be conjugated with a target compound (nicotine hapten) to elicit nicotine specific antibodies in vaccinated subjects. The assembled particles will bear strong resemblances as enveloped viruses, which are commonly strong immunogens. Using carbon nanohorn as support will enable us to control the size of the vaccine, which will possess unparalleled stability and could be suitable for oral or intranasal administration. This proof- of-concept project is focused on developing the particle assembly process and test the immunogenicity of the particles. The specific aims are to 1) prepare carbon nanohorns with controlled size and surface modifications, 2) assemble nanohorn supported lipid particle with carrier protein embedded and conjugate hapten molecules to the carrier protein, and 3) evaluate the immunogenicity of the vaccine in mice. Antibody titer and antibody-nicotine binding affinity of current vaccines, particularly NicQb by Cytos AG, will be used as the benchmarks to evaluate the success of this vaccine candidate. Success of this project will pave the way for investigating the effects of various parameters, such as nanohorn size, lipid composition, and number of embedded carrier protein per particle, on the efficacy of the vaccine. Moreover, we fully recognize the importance for the toxicological study of the assembled particles. However, due to the limited timeline and budget, only basic toxicological signs will be observed and assessed during the animal test. Full scale toxicological and safety study will be carried out in the next phase of the project. In addition, the possibility of administering the vaccine through oral or intranasal route will be evaluated in the next phase of study if this proof-of-concept study is successful. The broad impact of this project resides in the potential of a new platform technology for producing much needed and effective vaccines against various drug molecules. It is highly possible that this technology will revolutionize the treatment of psychoactive drug addiction. PUBLIC HEALTH RELEVANCE: Psychoactive drug addiction is a growing global problem and causes significant social and economical stresses. Pharmacological treatments of drug addiction have limited success with serious side effects. On the other hand, immunopharmacotherapy has shown tremendous promises, but current vaccines have not been able to elicit high antibody titers in the vaccinated subject for the vaccines to be highly effective. Thus, there is a strong need for developing highly effective vaccines against drug additions. This project will target this need directly by developing novel vaccines for the treatment of drug addiction. These vaccines will likely possess greater stability and immunogenicity when compared with the current vaccines.